www.fisiokinesiterapia.biz

CELLULE SNEDCELLULE SNED

Contenuto di granuli Contenuto di granuli secretorisecretori

Chromogranins

Synaptophysyns, VCAM 2

PGP 9.5-NSE

Secretory process

Circulating CGA, 5HT and othersnon specificsecretion markers

Citolysis

Circulating NSE

Receptors

Adhesion moleculesCD 44

CD 56

CD 171

CD 24

CD 57

p53

menin

RET

Insulin, gastrin,

PP, glucagon and other specificsecretion markers

from Ferolla et al. modified

cAMPCa++

Phosphatase

CalcineurinPTP

Ser/ThrPhosp.

da Patel, J.En.Inv. (1997) modif.

SSTRSSTR

Carcinoid Tumors: HistoryOberndorfer: introduced the term “Karzinoid” to describe a class of intestinal tumors thatbehave less aggressively than adenocarcinomas

•1914 Gosset and Masson: using silver impregnation techniques demostrated that carcinoid tumors might arise from enterochromaffin cells (Kulchitsky’s cell) within glands of Lieberkuhn

•1928 Masson: established characterization of carcinoids as Argentaffin cell tumors

•1954 Waldenstrom’s group: described a series of patients with “carcinoid syndrome”

•1968 Pearse: Concept of APUD System

•1980 WHO classification: applied the term carcinoid to all tumors of the diffuse endocrine system (synonymous with neuroendocrine cell system).

DiMISEM

Classificazione dei tumori neuroendocrini

1. Tumori endocrini ben differenziati:-a comportamento benigno(carcinoide tipico)-a comportamento incerto (carcinoide atipico)

2. Carcinoma endocrino ben differenziato3. Carcinoma endocrino scarsamente differenziato

(a piccole, intermedie e grandi cellule) 4. Tumori misti esocrini-endocrini

(Solcia et al., 2000)

• Typical Carcinoid (TC)“with fewer than two mitoses per 2 mm2 of viable tumour and lacking necrosis.”(ten high-power fields)

Neuroendocrine Tumors

• Atypical Carcinoid (AC)“with between two and ten mitoses per 2 mm2 and/or with foci of necrosis.”(ten high-power fields)

Clinical featuresSymptoms Schrevens et al.

Lung cancer 2004

– Asymptomatic 23%– Recurrent infections* 42%– Cough / Hemoptysis * 21%– Chest pain 7%– Dyspnea / Wheezing **All had central tumors demonstarble by bronchoscopy

Endocrine symptoms: 12 %(Uppsala material) carcinoid syndrome, atypical carcinoid s., cushing, acromegalia

Endocrine secretion: 15 %(Perugia material) carcinoid syndrome, atypical carcinoid s., cushing, acromegalia

Carcinoid TumoursFrequency % Secretory Products

Foregut (10-15%)Thymus ACTH, CRF, GHRH, ADHLung Serotonin, Histamine, Gastrin,

Calcitonin, Tachykinis, CgA, HCGα/βStomach CgA, Histamine, Gastrin, Serotonin,

Gastrocalcin?Duodenum Gastrin, Somatostatin, CgA

Midgut (20-60%)Appendix No known secretory productIleum Caecum Serotonin, Tachykinins, CgAColon ascendence

Hindgut (25-30%)Colon CgA, PP, HCGaRectum PYY, Somatostatin

}

• CARCINOIDS

• INSULINOMAS

• GASTRINOMAS

• VIPOMAS

• GLUCAGONOMAS

• SOMATOSTATINOMAS

• GRF-OMAS

Clinical syndromecorrelated to peptidehyperproduction

NEUROENDOCRINE FUNCTIONING TUMORS

La “Sindrome da Carcinoide”

CARCINOID SYNDROME

ATYPICAL 5%

Prolonged flushingHeadacheLacrimationBronchoconstriction

TYPICAL 95%

FlushingDiarrheaWheezingCardiac fibrosis

GASTRINOMA and Zollinger Ellison Syndrome

UlcersReflux symptomsDiarrhea

SYMPTOMS and SIGNS TUMOR DISTRIBUTION

< 10%

20%

60-80%

VIPOMA

Watery DiarrheaHypokaliemiaHypoachlorhydriaHypercalcemiaFlushing

TUMOR DISTRIBUTION

SYMPTOMS and SIGNS

~5-10%

~90%

GLUCAGONOMA

Migratory Necrolityc ErythemaDiabetesWeight loss TUMOR DISTRIBUTION

SYMPTOMS and SIGNS

14%51%

22%

SOMATOSTATINOMA

CholelithiasisDiabetesDiarrhea/Steatorrhea

TUMOR DISTRIBUTIONSYMPTOMS and SIGNS

57%43%

• CARCINOIDS

• INSULINOMAS

• GASTRINOMAS

• VIPOMAS

• GLUCAGONOMAS

• SOMATOSTATINOMAS

• GRF-OMAS

Clinical syndromecorrelated to peptidehyperproduction

NEUROENDOCRINE FUNCTIONING TUMORS

M.E.N. (Multiple Endocrine Neoplasia)Definizione

Gruppo di Neoplasie che hanno in comune le seguenti caratteristiche:

1. Secernono uno o più Peptidi o BioAmine2. Sono Tumori in genere benigni, con effetti clinici indotti

da ipersecrezione di ormoni3. I Tumori compaiono abbastanza precocemente

interessando spesso più organi endocrini4. Esiste la possibilità di trasformazione maligna5. Eredità con modello autosomico dominante

M.E.N. type 1: common features

• Parathyroids hyperplasia (85-90%)• Pituitary adenomas (15-50%)• Pancreatic tumours (30-80%)• Carcinoids (5% ?)• Lipomas (5%)• Adrenocortical adenomas (10-15%)• Thyroid adenomas (5-20%)• Thymic Carcinoid ?

““two hittwo hit”” model of model of tumourtumour developmentdevelopment

inherited (germline) inactivation of one copy of a tumoursuppressor gene

(FIRST HIT)(FIRST HIT)

subsequent (somatic) mutation

(SECOND HIT)(SECOND HIT)

inherited syndrome associated tumor development

From Trend in Endocrinol and Metab 2001May; 12 (4): 173-8

MEN 2A

Carcinoma midollare della tiroide 90-100%

Iperplasia delle paratiroidi 10-50%

Feocromocitoma bilaterale 40-50%

MEN 2B

Carcinoma midollare della tiroide 90-100%

Feocromocitoma bilaterale 50-70%

Neuromi mucosi 90%

ret

GDNF

Extracellular

region

Plasma

membrane

GDNF-α

ligand-binding

domain

C634

M918

tyrosine kinasedomains

Intracellular

region

GDNF

GDNFR-αRET

TK918

TM

Cys-rich

634

Germline ret mutation in multiple endocrine neoplasia type 2 families

MEN 2A 98% Codon 634 in85%(usually TGC toCGC)

FMTC 88% Codon 634 in30% (usuallyTCG to TAC)Codon 634 TGCto CGC notfoundCodon 618 in33%Codon 768 and804 rarely

MEN 2B 95% Codon 918(ATGto ACG) in 100%

(data from the International Ret Mutation Consortium)

Angiofibroma Collagenoma